Mitochondrial occupy a central role in cellular homeostasis, particularly by satisfying cellular energy needs, and, paradoxically, also occupy a central role in a range of disease processes. Mitochondria are the major source (>90%) of adenosine triphosphate (“ATP”), which is used in a range of energy-requiring biochemical and homeostatic reactions in the body. Mitochondria are also a major source of reactive oxygen species (“ROS”), which are involved in the etiology and progression of a range of disease processes, including, for example, inflammation, stroke, cardiovascular disease, cancer, diabetes, neurodegenerative diseases (e.g., Alzheimer's Disease, Parkinson's Disease), drug- and chemical-induced toxicity, alcohol-induced liver damage, and aging-related diseases.
Antioxidant mechanisms in the body counteract the deleterious effects of ROS. These antioxidant mechanisms may, however, be overwhelmed during the development and progression of disease processes. The hydrophilic tripeptide glutathione (L-γ-glutamyl-L-cysteinylglycine) is an important antioxidant compound. Unlike lipophilic antioxidants, which must be provided by the diet, glutathione is synthesized in the body, particularly in the liver. Glutathione is present in mitochondria, but mitochondria lack the enzymes needed for the synthesis of glutathione (Griffith and Meister, “Origin and Turnover of Mitochondrial Glutathione,” Proc. Natl. Acad. Sci. USA 82:4668-4672 (1985)), and the mitochondrial glutathione pool is maintained by transport from the cytosol into the mitochondria. The mitochondrial glutathione pool amounts to approximately 15% of total cellular glutathione (Meredith and Reed, “Status of the Mitochondrial Pool of Glutathione in the Isolated Hepatocyte,” J. Biol. Chem. 257:3747-3753 (1982)). Although the mitochondrial glutathione pool is relatively small, it plays a key role in cytoprotection against ROS, and the depletion of mitochondrial glutathione concentrations is associated with cell damage and death (Meredith and Reed, “Depletion in vitro of Mitochondrial Glutathione in Rat Hepatocytes and Enhancement of Lipid Peroxidation by Adriamycin and 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU),” Biochem. Pharmacol. 32:1383-1388 (1982); Shan et al., “Selective Depletion of Mitochondrial Glutathione Concentrations by (R,S)-3-hydroxyl-4-pentenoate Potentiates Oxidative Cell Death.,” Chem. Res. Toxicol. 6:75-81 (1993); Hashmi et al., “Enantioselective Depletion of Mitochondrial Glutathione Concentrations by (S)- and (R)-3-hydroxy-4-pentenoate,” Chem. Res. Toxicol. 9:361-364 (1996)). In particular, depletion of mitochondrial glutathione concentrations sensitizes organs to cytokine (TNF)-associated cell damage (Colell et al., “Hepatic Mitochondrial Glutathione Depletion and Cytokine-mediated Alcoholic Liver Disease,” Alcohol Clin. Exp. Res. 22:763-765 (1998); Colell et al., “Selective Glutathione Depletion of Mitochondria by Ethanol Sensitizes Hepatocytes to Tumor Necrosis Factor,” Gastroenterology 115:1541-1551 (1998)). The antioxidant activity of glutathione is associated with its thiol group.